(a) Field of the Invention
This invention relates to pharmaceutical compositions containing a class of 5-phenyl-1,3-dioxoalkenyl compounds useful as inhibitors of leukotriene biosynthesis. This invention also relates to the use of 5-phenyl-1,3-dioxoalkenyl compounds as inhibitors of leukotriene biosynthesis. By inhibiting leukotriene biosynthesis, the 5-phenyl-1,3-dioxoalkenyl compounds of this invention are useful in preventing or alleviating conditions associated with leukotrienes, such as allergic reactions, inflammatory conditions, certain skin disorders, hyperalgetic conditions, and coronary vasoconstriction.
Arachidonic acid is converted enzymatically to various biologically active products, such as prostaglandins, thromboxanes, various hydroxyeicosatetraenoic and hydroperoxyeicosatetraenoic acids, and leukotrienes. The leukotrienes, products of the 5-lipoxygenase pathway, are implicated in allergic reactions, particularly asthma, see M. Griffin et al., N. Engl. J. Med., 308, 436-439 (1983); inflammatory conditions; skin diseases such as psoriasis; hyperalgetic conditions, see J. D. Levine et al., J. Neuroscience, 5, 3025-3029 (1985); and coronary vasoconstriction. One leukotriene, LTD.sub.4, is the major active constituent of slow reacting substance of anaphylaxis (SRS-A), a potent bronchoconstrictor that is released during allergic reactions. See R. A. Lewis and K. F. Austen, Nature, 293, 103-108 (1981). When administered to humans and guinea pigs, LTD.sub.4 causes bronchoconstriction by two mechanisms: (1) directly by stimulating smooth muscle; and (2) indirectly through release of thromboxane A.sub.2, which causes contraction of respiratory smooth muscle. Because antihistamines are ineffective in the management of asthma, SRS-A is believed to be a mediator of the bronchoconstriction occurring during an allergic attack. LTD.sub.4 may also be involved in other inflammatory conditions such as rheumatoid arthritis. Furthermore, LTD.sub.4 is a potent coronary vasoconstrictor and influences contractile force in the myocardium and coronary flow rate of the isolated heart. See F. Michelassi et al., Science, 217, 841-843 (1982); J. A. Burke et al., J. Pharmacol. and Exp. Therap., 221, 235-241 (1982). Another leukotriene, LTC.sub.4 , is also a very potent bronchoconstrictor. A third leukotriene, LTB.sub.4, is associated with leukocyte chemotaxis, a phenomenon in which leukocytes migrate from the blood to an inflammatory site in response to chemical or biological stimuli, and may be involved in both acute and chronic inflammation. LTB.sub.4 also appears to be associated with rheumatoid spondylitis and gout. Thus, the 5-lipoxygenase inhibitors of this invention, by inhibiting the production of leukotrienes, may prevent or alleviate the allergic, inflammatory, and vasoconstrictive conditions associated with leukotrienes.
Non-steroidal antiinflammatory agents, such as aspirin, indomethacin, ibuprofen, and the like, inhibit prostaglandin biosynthesis by blocking the cyclooxygenase pathway of arachidonic acid metabolism. As a consequence, leukotriene levels may increase as arachidonic acid is metabolized along the 5-lipoxygenase pathway, producing allergic reactions. Administration of 5-lipoxygenase inhibitors of this invention may be effective in reducing undesirable side effects associated with non-steroidal antiinflammatory agents when administered separately or in combination.
See (1) P. Sirois, "Pharmacology of Leukotrienes" in Advances in Lipid Research, 21, 79-101 (1985); (2) M. K. Bach, "Inhibitors of Leukotriene Synthesis and Action" in The Leukotrienes: Chemistry and Biology, L. W. Chakrin and D. M. Bailey, eds., pp. 163-194 (Orlando: Academic Press, 1984); (3) M. K. Bach, Bioch. Pharmacol., 33, 515-521 (1984); (4) C. W. Lee et al., "Human Biology and Immunoreactivity of Leukotrienes" in Advances in Inflammation Research, 6, 219-225 (1984); (5) P. Sharon and W. F. Stenson, Gastroenterology, 84, 454-460 (1984); (6) E. L. Becker, Trends Pharmacol Sci., 4, 223-225 (1983); (7) Editorial, "Leukotrienes and Other Lipoxygenase Products in the Pathenogenesis and Therapy of Psoriasis and Dermatoses" in Arch. Dermatol., 119, 541-547 (1983); (8) B. Samuelsson, Science, 220, 568-575 (1983); (9) R. A. Lewis et al, Int. J. Immunopharmac., 4, 85-90 (1982); (10) M. W. Musch et al., Science, 217, 1255-1256 (1982).
Unlike earlier therapeutic agents that treat symptoms rather than causes, the compounds of this invention and the pharmaceutical compositions thereof block the formation of causative mediators of allergic and inflammatory conditions and are therefore useful in the treatment of allergic reactions, inflammation, and other conditions associated with leukotrienes.
This invention also relates to a process that permits the unexpectedly efficient and convenient preparation of the 5-phenyl-1,3-dioxoalkenyl compounds of this invention. More specifically, this invention relates to a process for preparing 5-phenyl-1,3-dioxoalkenyl compounds in improved overall yield and purity by condensing optionally substituted benzaldehydes with acetoacetate esters, acetoacetamides, and 2,4-alkanediones.
(b) Prior Art
Condensation reactions of acetoacetate esters, acetoacetamides, or 2,4-alkanediones of the general formula CH.sub.3 (C.dbd.O)CH.sub.2 (C.dbd.O)-R with benzaldehydes normally occur at the active methylene (CH.sub.2) group rather than at the methyl group. See, e.g., J. March, Advanced Organic Chemistry, 2nd edition, pp. 854-859 (New-York: McGraw-Hill Book Company, 1977). Condensation at the methyl group has been reported to occur only under harsher conditions or by using more elaborate procedures than employed in the process of the present invention. For example, one method for preparing 5-phenyl-3-oxoalkenoates requires formation of a .beta.-keto ester dianion (by addition of two separate strong bases), followed by addition of an aldehyde and dehydration of the initially formed alcohol. S. N. Hucklin and L. Weiler, Tetrahedron Lett., 4835-4838 (1971). Another method for preparing 5-phenyl-3-oxoalkenoates requires forming an enol silyl ether from the corresponding .beta.-keto ester dianion, followed by reaction with the aldehyde, generally in the presence of an activating reagent such as titanium tetrachloride. T.-H. Chan and P. Brownbridge, J.C.S. Chem. Comm. 578-579 (1979); T.-H. Chan and P. Brownbridge, J.C.S. Chem. Comm., 20-21 (1981).
A condensation procedure employing titanium tetrachloride under conditions similar to those used in the present invention has been published, but the product compounds disclosed, unlike those of the present invention, are formed by a condensation reaction at the active methylene group and not by reaction at the methyl group. W. Lehnert, Synthesis, 667-669 (1974); W. Lehnert, Tetrahedron, 28, 663-666 (1972).